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U Environmental health fni)nrtiwi Vcl. n. pp. *. 1U1 German Investigations on Morbidity and Mortality of Workers Exposed to Vinyl Chloride by H. Weber,* W. Rein!,* and E. Greiser' Two studies on mortality and morbidity of workers exposed to vinyl chloride monomer (VCM) which have been carried out on behalf of the Ministry of Labour, Health and Social Affairs on Northrhine-Westphalia are reported. Vinyl Chloride Mortality Study The aims of this study were to determine stan dardized mortality ratios (SMR) for male workers exposed to VCM,' using the mortality rates of the West German male population as reference, to study the SMRs of a cohort of workers of the chemical industry comparable concerning age dis tribution and observation period but no; exposed to VCM and to determine the SMR of a cohort of workers in PVC-processing plants. The study was designed as a historic cohort study, covering the period from the beginning of the VCM- and PVC-production in all of the German plants till the end of 1974. Table 1 shows the main characteristics of the three cohorts investigated. Only Germans and Austrians were included in data analysis because of insufficient mortality data on various foreign na tionals employed in German factories. To deter mine the mortality rates of Austrians, West Ger man rates were used. To calculate expectations of total mortality, the mortality rates of the adequate years have been used. To calculate expectations of specific causes of death for all years before 1968. the rates of 1968 have been used; for the following years the rates of the corresponding years. Follow ing the procedure applied by Tabershaw (i), *S;aa;licher Gfwerbearr.. Dusseldorf. W. Germany. ^Diabetes Research Institute at the University o' Dusseldon". Division of Medical Statistics and Epidemioiog}. Dusselrior:'. W. Germany. October 19S1 weighting of observed cases of specific causes of death according to unknown causes of death has been done with weighting factors calculated sepa rately for three observation periods (up to 1959, 1960-1969. 1970-1974) as well as for six age groups. In all of the cohorts, follow-up rates nave been near or above 909c. The percentage of causes of death that could not be investigated due to loss or deletion of death certificates varied from 7.39c to 13.1%. To calculate age-standardized mortality ratios of specific causes of death, weighting has been done according to the procedure used by Tabershaw and Gaffey (j) to compensate for unknown or unidentified causes of death. Table 2 displays total mortality as well as some of the relevant specific causes of death. It can be observed that the otherwise observed "healthy worker effect" cannot be demonstrated in the German cohorts exposed to VCM or employed in PVC-processing plants. In the VCM cohort there are significant eleva tions of SMR of malignancies of the lymphatic and hematopoietic tissues (ICM 200-209). and of malig nancies of the GI tract (1CD 150-159). The latter is due to the paramount elevation of SMR of tumors of the liver (1CD 155). It must be noted that there is a modest elevation of SMP, of tumors of the liver also in the cohort not exposed to VCM nor employed in PVC-processing plants. N`o obvious explanation for this observation can be offered. In addition elevated SMRs for ischemic heart disease (1CD 410-414) car; be found in all of the three cohorts. Due to methodological 95 VC6019 shortcomings of the study no assessment of cardio vascular risk factors has been made. Therefore these results are of minor interesL When subdividing the V CM-exposed cohort ac cording to time of exposure there is a clear-cut increase of the SMP. of liver tumors with time (Table 3). This seems to be highly suggestive of a time-response pattern. As it has been impossible to determine- concentrations of VCM retrospectively due to technological and methodological problems, no dose-response pattern can be established. How ever time of exposure seems to be the best avail able guess for dose. Subclassification according to observation period Table 1. Characteristics of study cohorts. Population (Germans -t- Austrians) Man years Follow-up completed till 12/31/74. Sr deceased Observed Expected Unknown causes of death No. Sc Total mortality (SMR) Foreigners (excluding Austrians) Deceased Group 1. VCM/PVC production 7.02) 73.734 93.2 4)4 435 30 7.3 95 SS2 6 Group 11. refer group 4.910 76.029 89.E 417 533 47 11.3 7E 711 6 Creep 111. PVC 4.007 52.896 92.1 360 380 47 13.1 95 1.454 10 Table 2. Standardised mortality ratios. 1CD E Cause of death VCMfPVC production Obs. SMP. Total mortality 140-209 Al) mahgnant tumors 140-199 Malignant tumors of organs 200-209 Malignancies of lymphatic and hematopoetic tissues ISO-159 Malignant tumors of G1 tract and peritoneum 155 Malignant tumors of the liver 191 Malignant tumors of the brain 410-414 Ischemic hear, disease <10 Acute myocardial 800-949 Accidents 414 94 79 15 _ T 45 12 2 91 66 61 95 112 103 214b 149* 1523b 162 127* 114 137* `Beyond 95% confidence interval (s?). bBeyond 99% confidence interval 12). Reference group Obs. SMR 417 7E 83 S3 4 4 S3 6 77 27 71 4 401* 2 184 115 131* 83 120 44 99 PVC processing Obs. SMR 360 95 62 S5 60 89 2 34 15 56 3 434 5 535* 96 158b 69 143" 32 no Table 3. Standardized mortality ratios by duration of exposure. ICD E Cause of death < 12 Obs. SMR Duration of exposure, months 13-16 6:1-120 Obs. SMR Obs. SMR > :121 Obs. SMF. Total mortality 140-199 200-209 150-159 155 191 Malignant tumors of organs Malignancies of lymphatic and hematopoetic tissues Malignant tumors of G1 tract and peritoneum Malignant tumors of the liver Malignant tumors of the brain 53 6 1 3 0 0 93 136 102 S3 67 130 96 74 20 86 22 1)6 31 115 92 4 186 5 2S7 5 249 101 12 135 13 173 17 156 - 2 874* 3 1525b 7 2526b " 0- 1 350 i 276 96 Environmental Health Perspectives VC6020 Table 4. Standardized mortality ratios by period of observation. 1CD E 140-199 200-209 150-159 155 191 Cause of death Malignant tumors Malignancies of lymphatic and hematopoeiic tissues Malignant tumors of G1 tract and peritoneum Malignant tumors of the liver Malignant tumors of the brain To 1959 Obs. SMR 12 160 1 147 270* 1 1282 1 557 Observation period 1960-69 1970-74 Obs. SMR Obs. SMR Total Obs. SMR 29 64 194 103 414 95 0 275b 5 16E 15 214b 13 94 24 ITT6 45 149* 3 834* S 2264 b 12 1523b 0 1 223 2 162 `Bevond 95% confidence interval. kBeyond 99% confidence interval. Table 5. Standardized mortality ratios by age. 1CD Cause of death Age grout ^ 24 25-34 35-44 45-54 55-64 * 65 Total Obs. SMR: Obs. SMR Obs. SMR Obs. SMR O'os. SMR Obs. SMR Obs. SMR Total mortality 10 68 45 111 65 104 90 101 105 80 90 103 414 95 140-199 Malignant tumors of organs 0 4 141 13 188* 19 141 22 76 21 100 79 103 200-209 Malignancies of lymphatic and hematopoetic tissues 0 2 194 4 303 4 264 3 162 2 197 15 214 150-159 Malignant tumors of G1 tract and peritoneum 0 3 397 10 365b 10 145 10 89 12 140 45 149b 155 Malignant tumors of the liver 0 0- 6 6865b 0 3 934 b 3 1664b 12 1523 191 Malignant tumors of the brain 0 0 0" 3 254 1 362 0 2 162 `Beyond 95% confidence interval. bBeyond 99% confidence interval. Table 6. Groups for subdivision of laboratory examinations. Group Specification A-l VCM/PVC production A-13 PVC processing B-l VCM/PVC production and PVC processing, work capacity loss < 20% B-ll VCM/PVC production and PVC processing, work capacity loss * 20% C-l Germans and Austrians C-Il Foreigners (Exri, Austrians) D-l Plants with high morbidity D-ll Plants with low morbidity Table 7. Bromsulfalein retention.* VCM/PVC pvc Production Processing Retention normal Retention abnormal Total 26 21 44 10 70 31 *Chi square) - .09 (p < 1%). October 19S1 Total 47 54 101 Table . Bromsulfalein retention.* Germans and Austrians Foreigners Retention norma) Retention abnormal Total 17 30 33 2) 50 51 *Chi square; = 6.25 (p < 2.5%). Total *1 / 55 101 Table S. Bromsulfalein retention.* Work caps- Work caps- citv loss citv loss < 20% > 20% Retention normal Retention abnormal Total 4) 6 32 22 73 29 *Cbi square; = 6.81 ip < 1%). Total ti 10) 97 VC6021 (Table 4) reveals a rather inconsistent pattern: malignancies of the lymphatic tissues (1CD 200-209) are significantly elevated in the sixties only, whereas SMRs for tumors of the liver increase till the end of the study period. This might be referred to differ ent latency periods for both kinds of malignancies, but other causes might likewise have contributed to these results. However, it has to be reported that the number of angiosarcomas confirmed histologi cally in the Federal Republic of Germany in pa tients previously exposed to VCM has actually come to 17 in contrast to mere 4 at the endpoint of the mortality study (12/31/1974). The distribution of SMRs by age (Table 5) demonstrates an obvious susceptibility of males aged 35-44 for malignancies in general as well as for malignancies of the liver. The data base for the German morbidity study consists of all of the reports of suspected cases of occupational disease due to VCM or PVC produc tion or PVC processing. The reference population for these reports has to be defined as the total normal < 120 MS/di pathol. > iz> mg/dl MG/DL NORMAL 1.0 PATHOL, ? 1.0 <* 2 20* Fjcure 2. Vinv] chloride morbidity study: oral glucose toler ance test, 120 min after loading (norma) 120 mg/dl). * r *'5- woric brant prodi (as f Prod repo had set c numi lyzec formmuci stud; inve* Ft> 269 t those app1; Ama. lions in al. reter difie tion AND PVC PROCESSING WORK CAPACITY LOSS AND PVC PROCESSING WORK CAPACITY LOSS > 20 * . ict'RE 1. mal 1.0). t invl chloride morbidity study: total bilirubin mor- 9S AND PVC PROCESSING WORK CAPACITY LOSS < ?o s AND PVC PROCESING WORK CAPACITY LOSS 2?o * Figure 3. Vinyl chloride morbidity study: reticulocytes tnormal Jo'S). Environmental Health Perspectives VC6022 Oct fl working population in 1974 in the above mentioned branches, i.e., 6,500 workers in VCM or PVC production and 42.800 workers in PVC processing (as given by the German Association of Plastic Producing Industries). Till the end of 1974 , 269 reports of suspected cases of occupational disease had been received. As there has been no consistent set of examinations performed on each of the cases, numbers of observations for various variables ana lyzed vary according to examination method per formed. Insofar as the results of this study are of much lower validity than those of the mortality study, one should regard them as hints for further investigations. Four attempts to subclassify observation on the 269 cases have been undertaken (Table 6). Only those results showing significant differences when applying (-tests or chi-square tests are so classified. Amazingly none of the more sensitive Jab examina tions of liver functions showed a marked difference in all of the subclassifications besides bromsulfalein retention. In this instance there is a significant difference when subdividing by VCM/PVC produc tion versus processing (Table 7). as well as by nationality (Table 8) and most pronounced when subdividing by extent of work capacity loss (Table 9). This latter result, however, must be expected when an effect of exposure on liver function is anticipated. An impairment of the excretory liver function is suggested by elevated total bilirubin values in the subgroup with work capacity loss greater than 20% (Fig. 1). There seems to be an impaired glucose tolerance in this group, although observed in a small subsample only (Fig. 2), as well as a lower number of reticulocytes (Fig. 3). The thromocvte count in both groups was the same. These results, however, lead to no sensible inter pretation. as all results attempts failed to standard ize the methods applied for thrombocyte counts by various laboratories. REFERENCES 1. Tabershaw. ]. R.. and Gaffey. 'V. R. Mortal):y study of workers in the manufacture of vinyl chloride and its poly mers. J. Occup. Med. 16: 509-51E (197-1). 2. Bails.-. J. C. Significance factors for the ratio of a Poisson variable to its expectation. Biometries 20: 639-643 (19611. i t i 1 October 1981 99 VC6023